HEPATOCELLULAR CANCER Hepatocellular carcinoma is one of the most common malignancies in the world, with approximately 1 million new cases recorded annually. Epidemiology Gender Hepatocellular carcinoma is the most common tumor in males worldwide, with a male-to-female ratio of 5:1 in Asia and 2:1 in the United States. Geography Tumor incidence varies significantly, depending on geographical location. In the United States, hepatocellular carcinoma represents < 2% of all tumors, whereas in the Far East and sub-Saharan Africa, this neoplasm occurs at an incidence of 150 per 100,000 population and comprises almost 50% of all diagnosed tumors. A study analyzing SEER (Surveillance, Epidemiology, and End Results) data has shown that the incidence of hepatocellular carcinoma is rising in both white and black populations in the United States, with a current incidence of about 3.4 cases per 100,000 in whites and 5.6 per 100,000 in blacks. Modeling of the spread of hepatitis C virus (HCV) suggests that this number may continue to increase dramatically. Age The incidence of hepatocellular cancer increases with age. The mean age at diagnosis is 53 years in Asia and 67 years in the United States. Race The incidence of hepatocellular tumors is higher in Asian immigrants and blacks than in whites. Survival In patients who undergo curative resection, the 5-year survival rate is approximately 20%. Recurrence is common, with metastases arising in the remaining liver, lungs, bone, kidneys, and heart. Most patients present with unresectable disease. Patients with unimpaired liver function who can undergo resection may experience significantly longer survival than those whose disease is not resected. Etiology and risk factors Hepatitis B The close geographic relationship between hepatitis B incidence and hepatocellular carcinoma rates is well recognized. In endemic areas of hepatitis B, approximately 90% of all patients with hepatocellular carcinoma are positive for hepatitis B surface antigen (HBsAg). The presence of the hepatitis B "e" antigen has been found to increase risk ninefold. The most compelling epidemiologic evidence of a causal relationship between hepatitis B infection and hepatocellular carcinoma is the observation of a significant decline in the incidence of childhood hepatocellular carcinoma after the introduction of a national immunization program in Taiwan. The hepatitis B "x" gene, which can interact with p53, has been a focus of recent study on the pathogenesis of hepatocellular carcinoma. Hepatitis C has also been implicated in hepatocellular carcinoma development. The molecular mechanisms of HCV infection and carcinogenesis are poorly understood. Unlike patients with hepatitis B infection, hepatocellular carcinoma patients infected with hepatitis C usually have cirrhotic livers at diagnosis; this finding suggests an extended period of infection (or hepatic damage) before malignancy develops. Alcohol Patients with alcohol(Drug information on alcohol)ic cirrhosis are at risk for hepatocellular carcinoma, but the addition of HCV infection increases that risk dramatically. Other possible etiologies include aflatoxin, hemochromatosis, hepatic venous obstruction, thorotrast (a contrast agent no longer used for radiologic procedures), androgens, estrogens(Drug information on estrogens), and α₁-antitrypsin deficiency. Signs and symptoms Nonspecific symptoms Patients usually present with abdominal pain and other vague symptoms, including malaise, fever, chills, anorexia, weight loss, and jaundice. Physical findings An abdominal mass is noted on physical examination in one-third of patients. Less common findings include splenomegaly, ascites, abdominal tenderness, muscle wasting, and spider nevi. Up to 10% of patients may present with an acute abdomen due to a ruptured tumor. Screening and diagnosis Presently, no organization recommends routine screening of average-risk, asymptomatic adults for liver, gallbladder, and biliary tract cancers. α-Fetoprotein is produced by 70% of hepatocellular carcinomas. The normal range for this serum marker is 0-20 ng/mL, and a level > 200 ng/mL is essentially diagnostic for hepatocellular cancer in the absence of chronic, active hepatitis B infection. In the presence of active hepatitis B infection, the diagnostic cutoff is considered to be at least 1,000 ng/mL. In the setting of hepatitis C infection, the cutoff for diagnosis of hepatocellular carcinoma has not been well studied, but the specificity of values > 200 ng/mL appears to be high. False-positive results may be due to acute or chronic hepatitis, germ-cell tumors, or pregnancy. Hepatitis B and C Given the association between hepatitis B and C and hepatocellular cancer, blood should be sent for hepatitis B and C antigen and antibody determinations. Imaging The initial diagnostic test in the symptomatic patient may be ultrasonography, as it is noninvasive and can detect lesions as small as 1 cm. Ultrasound findings should be followed up with more specific imaging. Triple-phase, high-resolution CT and contrast-enhanced MRI are the primary imaging modalities used to diagnose and stage hepatocellular carcinoma. Recent reports have documented a high number of false-positive results with CT angioportography (CTAP) and CT hepatic angiography (CTHA). CT scan predicts resectability in only 40%-50% of cases and does not accurately determine the functional extent of cirrhosis. Major difficulties arise when the liver parenchyma is not homogeneous and the lesions are smaller than 1 cm. Laparoscopy is useful for the evaluation of small tumors, the extent of cirrhosis, peritoneal seeding, and the volume of noninvolved liver and therefore may be used prior to open laparotomy for resection. Laparoscopic or intraoperative ultrasonography should be used to confirm preoperative imaging tests. The laparoscopic results may change surgical management in up to onethird of selected patients. High-risk patients should be screened for hepatocellular carcinoma using ultrasonography and serum α-fetoprotein levels. At present, however, there is no standard screening interval, and screening has not been shown to affect survival. Data suggest that, for screened patients, there is an increase in the proportion of cancers that are resectable. A study comparing 6-month and 12-month survival intervals in a cohort of HIV-infected patients with hemophilia showed no substantial benefit to more frequent screening. Pathology Three morphologic patterns of hepatocellular carcinoma have been described: nodular, diffuse, and massive. Diffuse and massive types account for > 90% of cases. The nodular type usually has multiple lesions in both lobes. Histologic arrangements Several histologic arrangements have been identified: trabecular, compact, pseudoglandular or acinar, clear cell, and a fibrolamellar variant, which is associated with a relatively favorable prognosis. Staging and prognosis The staging system for hepatocellular cancer is based on the number and size of lesions and the presence or absence of vascular invasion (Table 1). The Okuda staging system accounts for the degree of liver dysfunction and may better predict prognosis than the TNM stage. However, the Okuda staging system does not adequately predict resectability. Because of the limited value of standard staging, the most important factors determining survival are technical resectability of lesions and degree of dysfunction of the normal liver. Groups in Italy and China have created prognostic indices that may prove useful for making treatment decisions. Of the 5%-30% of patients who can undergo resection, factors associated with improved survival include curative resection, small tumor size, well-differentiated tumors, and normal performance status. Cirrhosis, nodal metastases, and an elevated prothrombin time are indicative of a poor prognosis, as are male sex, age > 50 years, poor performance status, duration of symptoms < 3 months, tumor rupture, aneuploidy, high DNA synthesis rate, hypocalcemia, vascular invasion, and a high serum α-fetoprotein level. Treatment SURGERY
Surgery is the form of treatment that offers the greatest potential for cure, even though only a small minority of patients will actually be cured. Unfortunately, many patients whose disease is thought to be resectable are clinically understaged preoperatively. Only stage I or II tumors have a significant likelihood of being resectable for cure. However, a large tumor may still be potentially resectable for cure. Moreover, contiguous involvement of large vessels (including the portal vein and inferior vena cava) or bile ducts does not automatically mitigate against a resection, especially in patients with a fibrolamellar histology, although such resections are considerably more difficult. Bilobar disease may be addressed with formal resection, tumor ablation techniques (eg, cryoablation, radiofrequency ablation, and ethanol injection ablation), or a combination of the two modalities. Contraindications to resection include imminent clinical hepatic failure (jaundice in the absence of biliary obstruction), hypoalbuminemia, ascites, renal insufficiency, hypoglycemia, prolongation of the prothrombin and partial thromboplastin times, main portal vein involvement, extrahepatic metastatic disease, or other comorbid diseases that would preclude surgery of any kind. Noncirrhotic vs cirrhotic patients Resection should be performed in all noncirrhotic patients when feasible. Resection of hepatocellular carcinoma in the presence of cirrhosis is more controversial due to its increased morbidity in this setting. Cirrhosis has been a major deterrent to resection in western nations. Resectability rates vary from 0%-43% for cirrhotic patients, whereas up to 60% of patients without cirrhosis undergo resection. Use of the modified Child-Pugh classification of liver reserve may guide the surgeon in preoperative assessment of liver function status and may aid in the selection of operable patients. When resection is performed in the presence of cirrhosis, Child class A patients fare better than Child class B or C patients. Survival rates at 5 years following resection range from 4%-36%, with noncirrhotic patients living longer than cirrhotic patients. Transplantation Owing to the risk of hepatic failure following resection in cirrhotic patients, transplantation has become an option for patients with hepatocellular cancer and cirrhosis. In a study of 181 patients with hepatocellular carcinoma, Starzl and Iwatsuki found similar overall 5-year survival rates in patients treated with transplantation vs resection (36% vs 33%). Survival rates were similar in the two groups when tumors were compared for TNM stage. However, survival was significantly improved in patients with concomitant cirrhosis if they were treated with transplantation. Tumor recurrence rates for stages II and III tumors were significantly lower after transplantation than after resection, but no differences were seen for stage IV tumors. Patients with cirrhosis and single tumors < 5 cm or multiple tumors (up to 3 with none > 3 cm) can be considered for transplantation. Larger tumors may be treated with resection when feasible. Chemoembolization followed by transplantation may be considered in selected patients. The use of transplantation is significantly limited by the scarcity and lack of immediate availability of donor organs. Recently, changes in the organ allocation system have decreased waiting times for patients with documented hepatocellular cancer.